Placebos Linked to Potential Harms in IBD Clinical Trials

In successful clinical trials of drugs for inflammatory bowel disease (IBD), patients who received a placebo were at significantly higher risk for potential harms, according to two systematic reviews.

In one review and meta-analysis of 47 induction therapy trials that included approximately 21,000 adults with moderate to severe IBD, risk of worsening disease activity was significantly lower in the treatment versus placebo groups (4.2% vs 8.5%; HR 0.48, 95% CI 0.40-0.59), reported Alex Ford, MD, of St. James University Hospital in Leeds in England, and colleagues.

Patients who received active treatment were also significantly less likely than those who received placebo to experience serious adverse events (4.8% vs 7.2%; HR 0.69, 95% CI 0.59-0.80) or venous thromboembolism (0.2% vs 0.4%; HR 0.45, 95% CI 0.21-0.94), Ford’s team reported in Lancet Gastroenterology & Hepatology. Numbers needed to treat to avoid adverse events were high for uncommon outcomes (452 for venous thromboembolism, for example), but much lower for more common outcomes (23 for worsening IBD activity).

Results were similar in the group’s second meta-analysis in the same journal looking at 45 maintenance therapy trials with approximately 16,500 patients. Active treatment groups were significantly less likely to experience serious worsening of IBD, serious adverse events, and withdrawal due to adverse events.

“These findings clearly show that in moderately to severely active ulcerative colitis and Crohn’s disease, even over the relatively short duration of an induction of remission RCT, there were small but statistically significant harms associated with not receiving an active drug and being assigned to placebo,” the study authors wrote.

The harms associated with placebo were likely due to a lower risk of adverse outcomes in patients receiving an active drug, rather than a true increase in risk associated with receiving placebo, the researchers noted.

However, they added: “The results of this meta-analysis should prompt reflection on the current clinical trial model in IBD, encouraging critical thinking about possible strategies to minimise placebo exposure. Alternative trial designs should be considered for future novel drugs for IBD.”

For IBD patients who have exhausted established medical therapies, “comparing a new active drug head-to-head against an existing gold standard drug that has already been used without success is unlikely to be ethical,” they wrote. Better options might be platform studies, Bayesian analysis of existing data on expected placebo response rates, or open-label active treatment.

In an editorial accompanying the studies, Fernando Gomollón, MD, of Zaragoza University in Spain, said the rising prevalence of IBD could reach approximately 1% of the global population by 2030. This increased prevalence will spur more drug development and necessitate more clinical trials.

However, for many patients, the inclusion of a placebo group is a key factor for declining to participate in clinical trials, obstructing recruitment processes and slowing down studies, Gomollón said.

“Challenges in the design of clinical trials in IBD still remain, but the information of these two revealing studies will be fundamental for the design of future trials in the field,” he wrote. “Moreover, considering these data for improving participant consent will be mandatory: patients and trialists should have access to them for making the right decisions.”

For both studies, Ford and colleagues searched MEDLINE, the Cochrane Central Register of Controlled Trials, and other databases for randomized, placebo-controlled drug trials reporting data on adverse events in adults with moderate to severe ulcerative colitis or luminal Crohn’s disease. The minimum treatment period was 4 weeks for induction therapy and 20 weeks for maintenance therapy.

The investigators extracted summary data, and they pooled data using a random-effects model. Key outcomes assessed included any treatment-emergent adverse event, any drug-related adverse event, infection, worsening of IBD activity, withdrawal due to adverse events, serious adverse events, serious infection, serious worsening of IBD activity, or venous thromboembolism events.

Both meta-analyses included only clinical trials of drugs shown to be effective for IBD. As a result, they may have overestimated the potential harm for patients in placebo groups, Ford’s group said. Another limitation was that not all adverse events associated with a placebo are captured over the course of a trial, especially if rare, and these events might not have been fully assessed, they noted.

The findings highlight the potential harms associated with receiving placebo in placebo-controlled IBD trials, “which might relate to a reduction in risk of these events with active drug and the need to counsel patients carefully about the possible consequences of enrolling in such studies,” the study authors concluded.

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